Azacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease
Détails
Etat: Public
Version: Final published version
Licence: CC BY-NC-ND 4.0
ID Serval
serval:BIB_30ECDE94A727
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Institution
Titre
Azacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease
Titre de la conférence
Biology of Blood and Marrow Transplantation
Editeur
Elsevier BV
Adresse
Honolulu, USA, 2016, 18-22 February
ISSN
1083-8791
Statut éditorial
Publié
Date de publication
03/2016
Peer-reviewed
Oui
Volume
22
Numéro
3
Série
Biology of Blood and Marrow Transplantation
Pages
S393
Langue
anglais
Résumé
Background
The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Tregs).
Objective
We investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) in a humanized murine model of transplantation, and described the impact of the drug on human T cells in vivo.
Methods
In order to induce xGVHD, human peripheral blood mononuclear cells (huPBMC) were administered intravenously in NOD-scid IL-2Rγnull (NSG) mice.
Results
AZA successfully improved both survival (p<0.0001) and xGVHD scores (p<0.0001). Further, AZA significantly decreased human T-cell proliferation as well as INF-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA administration significantly increased the function, proliferation and frequency of Tregs through demethylation of FOXP3i1 and higher secretion of IL-2 by conventional T cells due to IL2 gene promoter site 1 demethylation. Interestingly, among AZA-treated mice surviving the acute phase of xGVHD, there was an inverse correlation between the presence of Tregs and signs of chronic GVHD. Finally, Tregs harvested from the spleen of AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments.
Conclusion
These findings emphasize a potential role for AZA as prevention or treatment of GVHD.
The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Tregs).
Objective
We investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) in a humanized murine model of transplantation, and described the impact of the drug on human T cells in vivo.
Methods
In order to induce xGVHD, human peripheral blood mononuclear cells (huPBMC) were administered intravenously in NOD-scid IL-2Rγnull (NSG) mice.
Results
AZA successfully improved both survival (p<0.0001) and xGVHD scores (p<0.0001). Further, AZA significantly decreased human T-cell proliferation as well as INF-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA administration significantly increased the function, proliferation and frequency of Tregs through demethylation of FOXP3i1 and higher secretion of IL-2 by conventional T cells due to IL2 gene promoter site 1 demethylation. Interestingly, among AZA-treated mice surviving the acute phase of xGVHD, there was an inverse correlation between the presence of Tregs and signs of chronic GVHD. Finally, Tregs harvested from the spleen of AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments.
Conclusion
These findings emphasize a potential role for AZA as prevention or treatment of GVHD.
Mots-clé
Transplantation, Hematology
Web of science
Open Access
Oui
Création de la notice
29/07/2016 9:25
Dernière modification de la notice
08/07/2021 7:09
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